Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer
Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS). We further show that LDHB suppression upregulates STAT1, a negative regulator of SLC7A11, thereby reducing SLC7A11-dependent GSH metabolism. Our study uncovers a previously undefined mechanism of ferroptosis resistance involving LDH isoenzymes and provides a novel rationale for exploiting oncogene-specific ferroptosis susceptibility to treat KRAS-driven lung cancer.
Authors
- Yanyun Gao (ORCID: https://orcid.org/0000-0002-1226-3073)
- Ren‐Wang Peng (ORCID: https://orcid.org/0000-0003-1199-6520)
- Haiqing Zhong (ORCID: https://orcid.org/0009-0004-3403-7108)
- Ralph A. Schmid (ORCID: https://orcid.org/0000-0003-0699-079X)
- Patrick Dorn (ORCID: https://orcid.org/0000-0002-7203-3122)
- Geert van Geest (ORCID: https://orcid.org/0000-0002-1561-078X)
- Thomas M. Marti (ORCID: https://orcid.org/0000-0003-3005-220X)
- Rémy Bruggmann (ORCID: https://orcid.org/0000-0001-5629-6363)
- Haitang Yang (ORCID: https://orcid.org/0000-0002-8732-5910)
- Haibin Deng (ORCID: https://orcid.org/0000-0002-6823-313X)
- Nicola Zamboni (ORCID: https://orcid.org/0000-0003-1271-1021)
- Qinghua Zhou (ORCID: https://orcid.org/0000-0002-2598-7775)
- Yang Zhang (ORCID: https://orcid.org/0000-0002-8209-819X)
- Jingyi Zhang (ORCID: https://orcid.org/0000-0003-2316-6436)
- Liang Zhao (ORCID: https://orcid.org/0009-0004-5999-8976)
- Duo Xu (ORCID: https://orcid.org/0000-0002-4691-1761)
Institutions
- University of Bern (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- Fujian Medical University (CN)
- Bern University of Applied Sciences (CH)
- Central South University (CN)
- Shanghai Jiao Tong University (CN)
- Sichuan University (CN)
- University of Michigan (US)
- University Hospital of Bern (CH)
- Shanghai Chest Hospital (CN)
- ETH Zurich (CH)
- Martel (CH)
- Hunan Cancer Hospital (CN)
- Jiangsu Province Hospital (CN)
- Union Hospital (CN)
- Nanjing Medical University (CN)
Publication Details
- Journal
- Cell Death and Differentiation
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1038/s41418-024-01427-x
- Citations
- 25
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 10.47
Funders
- National Science Foundation
- University of Bern
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Krebsliga Schweiz
- China Scholarship Council
- Swiss Cancer Research Foundation